Fluorocyclopropanes as inhalation anesthetics

ABSTRACT

NEW COMPOUNDS 1-CHLORO-1,2,2-TRIFLUOROCYCLOPROPANE AND 1-BROMO-2,2-DIFLUOROCYCLOPROPANE HAVE BEEN FOUND USEFUL AS GENERAL INHALATION ANESTHETICS.

United States Patent 3,825,606 FLUOROCYCLOPROPANES AS INHALATIONANESTHETICS Gerald J. ONeill, Arlington, Charles W. Simon, Bedford,

and Charles A. Billings, Concord, Mass., assignors to W. R. Grace 8:Co., Cambridge, Mass. No Drawing. Filed June 2, 1972, Ser. No. 258,957Int. Cl. C07c 23/04 US. Cl. 260-648 F 1 Claim ABSTRACT OF THE DISCLOSURENew compounds 1-chloro-1,2,2-trifluorocyclopropane and1-bromo-2,2-difluorocyclopropane have been found useful as generalinhalation anesthetics.

THE PRIOR ART Although a certain number of halogenated hydrocarboncompounds have joined the ranks of useful anesthetics in the recentpast, little has been added to the understanding of the mode of actionof chemical compounds in this physiological role, and the relationshipsof the difierences between fairly closely similar compounds with eithertheir toxic or therapeutic properties remain substantially unidentified.In view of this situation, the discovery of additional substancespossessing a desirable combination of properties for anesthetic purposesstill lies beyond the scope of routine expertise.

SUMMARY OF THE INVENTION It has now been discovered that newlysynthesized 1- chloro-1,2,2-trifluorocyclopropane and1-brorno-2,2-difluorocyclopropane possess high potency as generalanesthetics when administered to inhalation-anesthetic-susceptibleorganisms.

DETAILED DESCRIPTION The two halocyclopropanes disclosed herein for thefirst time are new compounds which have been found to possess anestheticproperties.

The compounds can be prepared by the reaction of a CF -carbene with anolefin according to the method of P. B. Sargent [.I. Org. Chem. 35 (3),678-82 (1970)]. The CF -carbene is obtained by thermal splitting fromhexafluoropropylene oxide, a compound that can be synthesized withrelative case [J. Org. Chem. 31, 2312 (1966)]. The reactions involvedmay be illustrated as follows:

It should be noted that this method of synthesis does not always yieldthe compound desired possibly because, in some instances, either thecyclization does not take place or, if it does, the resultingcyclocompound is unstable at carbene generating temperatures.

EXAMPLE 1 To prepare the chlorocyclopropane compound of the presentinvention, 4t-butylpyrocatechol, 1 part by weight, is placed in astainless steel autoclave. The autoclave is sealed, evacuated, andcooled to --78 C. l-Chloro-lfluoroethylene, 80.5 parts, andhexafluoropropylene oxide, 40.3 parts, are then introduced into theapparatus. The system is heated for 8 hours at 185 C. After cooling toroom temperature, the contents of the autoclave are tranferred to a 196C. trap. Materials boiling below 3,825,606 Patented July 23, 1974EXAMPLE 2 To obtain the bromocyclobutane compound,4-t-butylpyrocatechol, 1 part by weight, is placed in a stainless steelautoclave. The autoclave is sealed, evaci ated, and cooled to 78 C.l-Vinyl bromide, 116.2 parts, and hexafluoropropylene oxide, 46.4 parts,are then introduced into the apparatus. The system is heated for 8 hoursat C. After cooling to room temperature, the contents of the autoclaveare transferred to a 196 C. trap. Materials boiling below roomtemperature are allowed to escape and the residue is purified bypreparative vapor chromatography. The product has a molecular weight of157, a boiling point of 68 to 685 C. and a d, of 1.725 g./ml.

EXAMPLE 3 The physiological effects of the two fluorocyclopropanes weredemonstrated as follows, using a standard test for evaluation ofinhalation anesthetics similar to that described by Robbins [.l.Pharmacology and Experimental Therapeutics 86, 197 (1946)].

Mice were exposed to the anesthetic for a period of 10 minutes in arotating drum. Observations were then made of the pinch reflex, thecorneal reflex and the return of the righting reflex. At least fourgraded doses were employed to determine the minimum concentrationrequired to anesthetize 50% of the mice used (AC and the minimumconcentration required to kill 50% of the mice (L6 The anesthetic index(Al) was then calculated from these minimum concentrations. The resultsof these tests are summarized in the following table.

ANESTHETIC PROPERTIES Percent volume AI 1 an, Cyclopropane AC LCw A050)1-chlor0-1,2,2-triflu0ro-- 4 8 2 1-bromo-2,2-dlfiuro- 1. 5 4 2-3 1 Whentwo figures are given, the actual value of the anesthetic index liesbetween these two figures.

References Cited UNITED STATES PATENTS 3,349,136 10/1967 Boudakian etal. 260-648 F 3,634,525 1/ 1972 Barkdoll et al. 260-648 F OTHERREFERENCES Braker, Chemical Abstracts, vol. 71, p. 112462 (1969).

LEON ZITVER, BERNARD HELFIN, Primary EX- aminers N. CHAN, AssistantExaminer US. Cl. X.R. 424-352

